Multiple myeloma acquires resistance to EGFR inhibitor via induction of pentose phosphate pathway

被引：26

作者：

Chen, Yan ^{[1
]}

Huang, Ruibin ^{[1
]}

Ding, Jianghua ^{[1
]}

Ji, Dexiang ^{[1
]}

Song, Bing ^{[1
]}

Yuan, Liya ^{[2
]}

Chang, Hong ^{[1
]}

Chen, Guoan ^{[1
]}

机构：

[1] Nanchang Univ, Dept Haematol, Affiliated Hosp 1, Nanchang 330006, Peoples R China

[2] Jiangxi Acad Med Sci, Dept Haematol, Nanchang 330006, Peoples R China

来源：

SCIENTIFIC REPORTS | 2015年 / 5卷

关键词：

ACTIVATING MUTATIONS; K-RAS; KRAS; INSTABILITY; EXPRESSION; AUTOPHAGY; LEUKEMIA; CANCER; NRAS;

D O I：

10.1038/srep09925

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Multiple myeloma (MM) was characterized by frequent mutations in KRAS/NRAS/BRAF within the EGFR pathway that could induce resistance to EGFR inhibitors. We here report that EGFR inhibition solely exhibited moderate inhibition in KRAS/NRAS/BRAF wildtype (triple-WT) MM cells, whilst had no effect in myeloma cells with any of the mutated genes. The moderate inhibitory effect was conferred by induction of pentose phosphate pathway (PPP) when cells were treated with Gefitinib, the EGFR inhibitor. Combination of Gefitinib with PPP inhibitor 6AN effected synergistically in triple-WT cells. The inhibition could be restored by addition of NADPH. Dual EGFR/ERBB2 inhibitor Afatinib also exhibited similar effects. Further genetic silencing of EGFR, ERBB2 and mTOR indicated that major effect conferred by ERBB2 was via convergence to EGFR pathway in MM. Our results contributed to the individualized targeted therapy with EGFR inhibitors in MM.

引用

页数：8

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